The $10 billion unicorn in INmune Bio: viruses as drivers of inflammatory neurodegeneration
- Carl Kestens
- Apr 25
- 11 min read
Updated: Apr 28
Summary
"Scientists have found new solution for the treatment of Alzheimer’s disease."
The media coverage of preclinical discoveries or results of meta-analyses highlighting a new development in the field of Alzheimer’s often bears titles similar to this one.
Titles like these could be a bit misleading. The disease is multifactorial, so readers may get confused as to which is the actual cause of the disease.
This blog discusses the involvement of viruses such as herpes simplex, Epstein-Barr, Covid-19 and bacteria such as p.gingivalis in neurodegeneration.
Inflammation, we will see, is the overarching principle.
Viruses, bacteria and toxins are part of each person’s allostatic load, the cumulative burden of stressors accumulated over the span of a lifetime.
The presence of microbes, even in a dormant state, allows chronic inflammation to exacerbate. Reducing dormant viral load is probably difficult. Prevention may be useful.
Reduction of the associated inflammatory load is probably the better approach.
Introduction
Shingles vaccines reduce dementia risk
The past weeks, some news headlines in the academic field discussed the finding that the shingles vaccine could reduce dementia risk. Shingles, Herpes Zoster, is caused by the Varicella Zoster Virus.
Two recently published studies, one of which in Nature, recently reported that receiving different shingles (Herpes Zoster) vaccines may reduce the risk of developing dementia later in life. There had been studies on that before, which were mostly observational and prone to confounding variables, but these studies were the most rigorous research to date on the subject. There are two shingles vaccines: Zostavax (now discontinued) and Shingrix.
The first study entitled (‘The recombinant shingles vaccine is associated with lower risk of dementia’), leveraging the U.S. switch from Zostavax to Shingrix, found that Shingrix was associated with a 17% higher chance of avoiding a dementia diagnosis.
The second and most recent study focused on Wales, using another shingles vaccine. Many countries have rolled out programs to vaccinate older adults against shingles. When a shingles vaccine program was rolled out for people in their 70’s living in Wales,
those who were turning 80 just after the start date were eligible for the vaccine, but those who had turned 80 just prior to the start date were ineligible and remained ineligible for life. This presented a natural experiment because these two groups of people were ideal comparison groups given that they were likely similar to each other in all ways except for the fact that their birthdays happen to fall on either side of a random date. It’s probably the closest natural experiment you get to a placebo-controlled trial. The trial showed that over a seven-year follow-up, dementia incidence was reduced by 20% among those eligible for the vaccine.
Both studies align well with previous research, including a pseudorandomized trial and a meta-analysis of four observational studies. The new study—led by Stanford researchers Markus Eyting and Pascal Geldsetzer— is considered to stand out for its rigor, having ruled out differences in other vaccinations, medication use, healthcare access, and other variables, and finding consistent results across populations in both England and Wales.
Interestingly, also, the effect of the first study was clearly not only related to Alzheimer’s dementia.
The Stanford team’s study also found that people who had multiple bouts of shingles were more likely to develop dementia, and those treated with antivirals were less likely, strengthening the case that reactivation of the Varicella Zoster Virus (VZV) might play a role in dementia development.
And so in an article called ‘Do viruses trigger Alzheimer’s?’ the Economist reported on these studies, quoting the big expert on the matter Ruth Itzhaki, and questioning the old paradigm of amyloid and tau as causes of the disease.
Prof. Ruth Itzhaki: focus on HSV-1 vaccine as trigger for Alzheimer’s
Prof. Ruth Ithzaki is an expert in the field when it relates to viruses as drivers of neurodegenerative diseases, who has mostly focused on herpes simplex virus in her research. She’s on STAT’s Status List 2025. Charles Piller covered her in her book, just like he covered Malù Tansey as part of the leading figures of the so-called ‘left field’, i.e. the persons whose studies did not primarily focus on amyloid and tau in Alzheimer’s disease over the past decades.
With the new studies on shingles vaccines, The Times considered Prof. Itzhaki vindicated in April 2025. Prof. Itzhaki had, on several occasions, stated that she had for years been neglected and been considered the left field.
Times change. Until 2021 and the mRNA vaccines had also been considered the left field. In 2023, Katalin Karikó is a Nobel Prize winner. I will discuss the Covid-virus and dementia risk later.
Prof. Itzhaki’s research showed, for example, how a herpes simplex virus could remain dormant and cause a latent infection, stimulating intracellular levels of β-amyloid peptides in neuronal and glial cells. An infection with this virus “produced changes which were very much like those that occur in Alzheimer’s disease,” such as the formation of amyloid plaques, neural inflammation, decreased functionality and the formation of gliosis. A paper by Baird et al. would be in the making focusing on other viruses showing the same effects.
The broader view: certain brain-penetrating viruses as cumulative drivers of neurodegenerative diseases
So, are the above-mentioned two herpesviruses the only ones that could be of influence on the development of Alzheimer’s? No.
"Growing evidence suggests that a number of different microbes all can trigger Alzheimer's in some people", says Dr. Anthony Komaroff, editor in chief of the Harvard Health Letter and professor at Harvard Medical School.
What is particular is that these viruses remain lifelong in one’s body, mostly in a dormant state. We usually think of a virus as an infectious agent that causes a short-term illness like a cold, and then we recover from it, but some viruses stay in the body after we've been exposed to them, and some of them can go on to cause chronic diseases. In healthy younger adults, the virus is kept dormant by the immune system, but as we age our immune system gets weaker and the virus is more likely to reactivate.
Some of these microbes have been found in the human brain regions most affected by Alzheimer's, and large studies show that the risk of developing Alzheimer's is much higher in people who have experienced a severe infection decades before.
Links have been made with herpes simplex virus 1 (cold sores) and 2 (genital sores), varicella-zoster virus (chickenpox and shingles), COVID-19 (and this is a bad one, long-covid possibly leading to an Alzheimer’s fallout in the coming years if we don’t start acting fast), bacteria that live in our mouth and cause gum disease (periodontitis) such as p.gingivalis (gingipains), and possibly also gut bacteria.
The evidence is abundant and spreads across neurodegenerative diseases.
A large Finnish study had been looking at several connection between microbes and neurodegenerative diseases, and had found the strongest association—a 31-fold risk elevation compared with controls—between Alzheimer’s and viral encephalitis. Encephalitis, or inflammation of the brain. No viral infections were associated with a protective effect against a neurodegenerative disease, and nearly all of the viral-disease pairings involved “neurotropic” viruses—those that can invade the central nervous system.
In 2022, specifically for Epstein-Barr virus (EBV), yet another herpes virus, EBV-infected cells, free virus load, and abnormally elevated EBV titers are observed in the cerebrospinal fluid. EBV can infect neurons directly, induce neuroinflammation and demyelination, and promote the proliferation, degeneration, and necrosis of glial cells, thereby contributing to the occurrence and development of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other diseases.
In 2023, a massive data mining study found numerous associations between common viruses like the flu and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and ALS.
Connections have been found between the influenza virus and Parkinson’s, and between genital warts (caused by human papillomavirus) and dementia.
The analysis of twenty years of data from the blood tests of 10 million U.S. soldiers reported that it’s nearly impossible to develop multiple sclerosis without first being infected with the Epstein-Barr virus.
Cairns and Ithzaki had shown that using the model in which the HSV-1 DNA has been made latent, infection with varicella zoster virus led to reactivation of the HSV-1 virus, with subsequent AD-like changes.
Vaccines could be somewhat preventative
Some vaccines appear to be somewhat preventative. The studies above on shingles have already highlighted that.
In 2022, a large retrospective study came out, covering 17 studies and looking at 1.857.134 participants, showing that vaccinations as such were associated with a 35% lower dementia risk. All types of vaccination were associated with a trend toward reduced dementia risk, with rabies, tetanus & diphtheria & pertussis, herpes zoster, influenza, hepatitis A, typhoid, and hepatitis B vaccinations being significant. Individuals with more full vaccination types and more annual influenza vaccinations were less likely to develop dementia. Gender and age had no effect on this association.
In a Nature article of April 17, 2025 entitled ‘The Pathogen Proposal’, Michael Eistenstein concludes that there are many links to viruses and Alzheimer’s disease, but that it is unclear whether viruses cause the disease, or whether vaccines amp up the immune system and thereby prevent the disease. I believe there to be a bit of both. In his article, under the chapter ‘An inflammatory hypothesis’, Mr. Eistenstein also explains that although historically Alzheimer’s research was dominated by plaques and tangles, there is now more focus on a strong inflammatory response that suppresses neuronal function and accelerates the formation of amyloid-β plaques and tau tangles, with amyloid-β being one of the causes, but lifestyle and environmental factors being others allowing for an inflammatory environment in the brain that favours the development of Alzheimer’s. One of these inflammatory source could be viral or bacterial infections.
In the right subpopulation, inhibitors could work (a bit)
In 2021, Cortexyme had reported a 57% slowing of cognitive decline in the 80 mg BID arm (p=0.02) and a 42% slowing in the 40 mg BID arm (p=0.07) vs. placebo. Cortexyme’s drug was a bacterial protease inhibitor, designed to inhibit p.gingivalis. Reductions in P. gingivalis in saliva at week 24 were significantly correlated with improved outcomes at the end of the treatment period as measured by ADAS-Cog11 (p=0.0007), CDR-SB (p=0.004) and MMSE (p=0.007).
As such, that subgroup effect would have been the best result to date. Combined, that’s about double the efficacy of anti-amyloid antibodies, but still far from stabilization. The effect logically did not translate to the overall patient population; not everyone that had this infection was enrolled.
Atuzaginstat also came with liver issues. And as the trial failed, the company eventually had to end development of that drug.
Similar to the afore-mentioned viruses, p. gingivalis induces an inflammatory response. The blood-brain-barrier is leaky in the presence of Alzheimer’s disease. Bacteria are able to access AD brains. Scientists showed that chronic periodontal bacterial infection increased circulating inflammatory mediators, initiated microglial cell activation, and had a direct impact on the survival of neurons. “Thus, the presence of a higher inflammatory burden as a result of systemic proliferation of bacteria, genetic susceptibility toward recurrent infections, and direct entry of bacteria (P. gingivalis) into the brain as a result of chronic bacterial infection would provide a catalyst capable of triggering cerebral injury.”
On (long-)Covid
Covid hit human kind especially hard in 2020 . The word ‘cytokine storm’ is long forgotten at this storm, but as a reminder: most hospitalized patients died not of respiratory failure, but due to a lethal cytokine storm, as the body was struggling to fight the infection. Logically there is less long-term data than in the other viruses, but it will come out one day. Covid is a big inflammatory trigger, despite high global vaccination rates.
Humanity also developed a new disease, unseen before on such a scale. They called it long-Covid. It’s neurological, they gave it the euphemism ‘brain fog’, it’s not peripheral, it’s severe, and it could lead to dementia at a much younger stage – if it’s not already dementia in the early stages.
In 2024, a case was reported of a 25-year old female having developed dementia and epilepsy after a Covid-infection.
A longitudinal study conducted in Ecuador assessed cognitive decline among individuals aged 40 and above who had mild symptomatic SARS-CoV-2 infection, finding 21% of seropositive individuals experiencing significant cognitive decline compared to 2% of seronegative individuals. A systematic review and meta-analysis published in 2022 analyzed 27 studies involving 2,049 individuals with a mean age of approximately 56 years, showing that patients who had recovered from COVID-19 exhibited impairments in executive functions, attention, and memory up to seven months post-infection, compared to healthy controls.
Some further articles:
The Impact of the COVID-19 Pandemic on Dementia Risk: Potential Pathways to Cognitive Decline: “Our hypothesis is that each injury consequence has the independent potential to contribute to long-term cognitive deficits with the possibility of progressing to or worsening pre-existing dementia. Already, reports from recovered COVID-19 patients indicate that cognitive alterations and long-term symptoms are prevalent.”
UK researchers find Alzheimer’s-like brain changes in long COVID patients
COVID-19 linked to higher dementia risk in older adults, study finds
COVID-19 linked to increase in biomarkers for abnormal brain proteins
Molecular cross-talk between long COVID-19 and Alzheimer’s disease
Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”: “pTau 217 and pTau 181 have been patented by Lilly and Simoa®® for AD; however, they could also diagnose long COVID“.
Apparently covid spread in the brain via so-called ‘tunneling nanotubes’.
In 2022, right after the end of the pandemic, an article was published comparing biomarker levels of Alzheimer’s among hospitalized COVID-19 patients without a history of dementia. Chosen biomarkers were total tau, p-tau181, GFAP, NfL, AB40/42 and others. The results showed that t-tau, p-tau181, GFAP, and NfL – AB40/42,for example - were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness.
The pandemic is done. But is it really? Or will we be seeing an exponentially growing (long-)Covid-fallout in a decade or two?
Allostatic inflammatory load as the only logical explanation for neurodegeneration
In my blog post of July 31, 2022, I explained that allostatic load, as the cumulative burden of stressors one encounters throughout life, causes the heterogeneity seen in Alzheimer’s. Allostatic load “[…] involves the interaction of different physiological systems at varying degrees of activity. When environmental challenges exceed the individual ability to cope, then allostatic overload ensues. Allostatic load is identified by the use of biomarkers and clinical criteria.” This includes genetics, environmental stressors, physical and bodily stress and strains put on the body because of one’s diet and level of exercise.
The present blog discussed part of that allostatic load, with a focus on viruses and bacteria as drivers of neurodegenerative diseases. Aggregated amyloid and phosphorylated tau are other drivers. Etcetera.
When I write ‘drivers’ of disease,, I mean that they have the potential to continue or to exacerbate the inflammatory loop glial cells are in, preventing these cells to return to their homeostatic nurturing state.
The practical solution to that allostatic load is not reducing each person’s triggers, but rather to reduce inflammation overall, selectively, not broadly. That’s what XPro does. And the results are already there, if one chooses not to ignore them (in a short report written by students that is ignorant of ptau-217 and NfL, for example).
Conclusion
The (dormant) presence of certain brain-penetrating viruses and bacteria can be linked to the faster onset or progression of dementia. There is abundant research in that regard, in which inflammation plays a primary role. In fact, neuroinflammation is the overarching principle which ties the different studies linking viruses and dementia risk together.
Just like amyloid and tau, viral and bacterial load will differ for each person, and I believe it would be erroneous to think that eliminating any such trigger may solve Alzheimer’s. There may be many other triggers of the inflammatory load accumulated over one’s lifetime.
These inflammatory triggers cause the glial cells in the CNS to deviate from their original activity, causing neurodegeneration.
The approach of reducing inflammation as such, selectively, allowing the glial cells to revert to their original function, in patients who have markers of inflammation, seems the most practical approach. And it has yielded effects, to those who want to look and understand the fast-evolving field of biomarkers in Alzheimer’s disease.
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